Nanotechnology: A pathway for sustainable innovation in drug development

It seems every effort to go green requires some sort of compromise whether that be price, performance, stability; whatever. Right now, electric cars are more expensive to buy than those with a conventional combustion engine. And they can’t go anywhere near as far.

Of course, we all recognise that very soon those compromises will become less evident as the drive towards a more sustainable world gathers every increasing pace and consequently the solutions improve in performance.

But there are already some areas in the pharma supply chain where going green needn’t cost you the earth in terms of performance. In this article we will explore how bottom up nanotechnology can deliver oral and injectable APIs with enhanced bioavailability, increased solubility and improved stability, sustainably.

We will explore the sustainability challenges which the current ‘gold standard’ approach faces and demonstrate how bottom up approaches to nanotechnology require a considerably lower equipment footprint, a significant reduction in energy consumption. All achievable without any compromise on performance, timescale or cost.


From the icecaps to the rainforests via the oceans, there is no shortage of visual evidence reminding us that today’s global economy can have a very direct impact on the world around us.

In recent years, growing awareness of the extent of this impact has triggered an environmental awakening in consumers and businesses alike. Campaigns have been launched and corporate priorities adjusted in order to align behaviours and models with a more sustainable future.

For the pharmaceutical sector, where the ultimate goal is to improve health outcomes, an increasing emphasis is being placed on adapting existing approaches and adopting new ones that give consideration to the ongoing welfare of our planet.

These efforts to support sustainability and limit environmental impact are being felt across the entire supply chain. Major pharmaceutical companies have publicly committed to achieve carbon reduction goals and, in some cases, even carbon neutrality as part of ambitious Corporate Social Responsibility programmes.

It is a difficult yet important challenge, and one the industry can meet by embedding sustainable thinking across all operations, from IT and finance through to R&D and manufacturing. Indeed, drug development, the cornerstone of activity among pharmaceutical companies, is another business area that will need to be carried out with growing consideration for aspects such as energy consumption, materials wastage and the potential for causing pollution.


Drug development, for a significant number of pharmaceutical companies in today’s market, is an area increasingly focused on the benefits of nanotechnology, whether for New Chemical Entities (NCEs) or in the repurposing of existing APIs. Since 1970, the Center for Drug Evaluation and Research (CDER) within the US Food and Drug Administration (FDA) has received more than 600 submissions of human drug products containing nanomaterials. Furthermore, half of all of those were received within the last ten years, reflecting the acceleration in nanotechnology’s growth since the turn of the century1.

One of the main reasons that nanotechnology has attracted ever greater levels of attention is thanks to its strengths in addressing the issues of solubility and stability. Oral administration methods continue to offer high levels of convenience for patients and support high levels of compliance, meaning it remains the preferred administration method for drug formulations, accounting for 62% of all FDA-approved pharmaceutical products2. Drugs administered in this way achieve the level of bioavailability required by demonstrating sufficient levels of aqueous solubility to be dissolved in the gastro-intestinal tract (GIT).

But while this quality is highly prized, for many it remains just out of reach. An estimated 80% of APIs currently under development suffer from poor aqueous solubility, with high lipophilicity (known as ‘grease ball’) or high hydrophobicity (known as ‘brick dust’) commonly cited as reasons for abandoning formulations that may otherwise show promise in addressing unmet medical needs.

While a degree of lipophilicity is required to penetrate the membrane, high levels mean that the molecule may remain inside the membrane rather than passing through. Molecules must also be in solution and in a neutral state for diffusion across the cell membrane to be successful. Whilst nanotechnology cannot change the intrinsic properties of a molecule, it can provide a novel route to overcoming the solubility challenge. At the scale of nano, molecules possess a superior surface area to volume ratio and, therefore, solubility characteristics and dissolution rates are improved.

Further to its benefits in oral administration methods, nanotechnology’s strengths are also being exploited for parenteral administration driven by a combination of NCE development, mRNA and repurposing for COVID-19 solutions. Over the last decade, its use has evolved from simple solutions to facilitating the development of more complex offerings in terms of both solubility and stability.


These qualities mean nanotechnology has become an area of great importance to pharmaceutical companies and their drug development programmes. Indeed, the potential to introduce greater chance of success to the development of new chemical entities (NCEs) addresses one of the key areas of risk in the inherently high-risk, high-cost R&D lifecycle. Although pharmaceutical companies typically employ techniques to enhance bioavailability at a later stage in development, its introduction earlier within the process can also bring greater efficiency to the overall process. Importantly, any savings measured in terms of time, resource and cost also translate into reduced levels of energy consumption.

Clearly, NCEs are far from the only area where nanotechnology can bring benefits. It is also opening new avenues for existing APIs, enabling them to be re-evaluated to explore the possibility of how, at nanoscale, they can address new disease areas or improve delivery. This is attracting significant interest in the area of generics, for example, where so-called supergenerics are the product of successful efforts to reap new rewards from drugs whose credentials in terms of safety and efficacy are already proven.

In a similar vein, by addressing shortcomings in the area of oral bioavailability, nanotechnology is enabling new life to be breathed into drug candidates that have either previously been deemed to have failed or whose development may have been placed on hold.


Repurposing drugs in this way has been brought into sharp focus this year with the outbreak of COVID-19. The novel coronavirus has had a devastating effect on populations across the world, and the pharmaceutical industry has urgently accelerated efforts to bring treatments to market. Given the timeframes involved in developing entirely new treatments, repurposing has taken centre stage, providing a model for rapidly reviewing existing drugs with a view to addressing the symptoms caused by COVID-19.

Researchers from the University of Cambridge were among those in the scientific community to advocate investigating the use of known antivirals to mitigate the effects of COVID‐19 alongside exploratory work to discover a vaccine exploration, suggesting a co-ordinated global approach to examining the spectrum of licensed drugs3. An example of this in action is remdesivir, an anti-viral initially targeted at hepatitis C and used to treat Ebola, that has now been given emergency use authorisation by the US Food and Drug Administration (FDA) for all hospitalised coronavirus patients, after having initially been indicated for only severe cases.

Repurposing, then, presents a significant opportunity for both patients and the pharmaceutical companies looking to innovate at speed and reduced cost, and nanotechnology has significant potential in supporting this approach. There is, however, no single, agreed pathway to nano success. There is a broad range of approaches under the wider nanotechnology umbrella, principally separated into ‘top down’ and ‘bottom up’ methods and carrier technologies, each of which has implications not only for characterisation and regulatory requirements but also for cost and energy consumption.


Wet milling or media milling, for example, which are common ‘top down’ techniques, employ abrasion to physically erode the API down to nano scale. In such environments, in order to produce molecules that meet the desired tolerances, several operation cycles may need to be completed, each of which may last for several days, bringing the need for large amounts of energy to be consumed in the process. It is estimated that particle-size reduction accounts for as little as 2% of the energy consumed during the milling process, with the remainder spent on deformation of particles, inter-particulate and particle-machine friction, heat, sound and vibration4.

A further example within the ‘top down’ bracket is high-pressure homogenization. As the name indicates, this is an energy intensive process, where in the course of milling, the drug particles are exposed to a power density of up to 1013 W/m3 – a level comparable to power densities observed in nuclear power stations5

Needless to say, the energy requirements and, therefore, environmental impact involved in such approaches is relatively high when compared with ‘bottom up’ continuous precipitation methods, which are characterised by higher levels of efficiency. The technology used by leon, for example, enables small molecules, peptides and hormones, including cytotoxic and high-potency oral and parenteral drugs, to be processed very cost-effectively, without the efforts associated with mechanical intervention. The drug is dissolved in a solvent and then combined with an antisolvent to precipitate stable crystalline or amorphous nanoparticles of uniform size down to 10nm.

This precipitation method can also be simply and quickly scaled-up from the bench to larger scale since the nanoparticle production process is identical in the development phase as it is for commercial production. While it is slightly larger in scale, the footprint of the equipment can easily be integrated into the production facilities of any CMO. This efficient pathway not only means less API is required for screening and validation, it means that decisions about likely success can be made with greater confidence earlier in the process and the journey to GMP production can be achieved faster, at lower risk and cost and, again, consuming less energy in the process.

The cost-effectiveness of this highly efficient technique is really exposed at the point of scaling to commercial production. While wet milling requires an investment of approximately €20–30 million, GMP commercial production equipment based on leon’s technology represents an outlay of less than €1.5million.


Underlying this economic argument for creating nanoformulations using bottom-up precipitation techniques is an important environmental argument. From the scalable manufacturing process to the potential for rapidly repurposing existing APIs, efficiency is embedded into the model. Indeed, in the case of leon, this quality is amplified by our strong network of alliance partners, which streamlines multi-stakeholder engagement into a unified offering.

All of this means that, along with time and cost, energy consumption and carbon impact are inherently kept to a minimum. It may even extend all the way to the patient, who receives the convenience of orally administered drugs with greater bioavailability at lower dose which limits the waste and other complications associated with higher or more frequent dosing and can lead to better compliance outcomes.

Taken together, this shows how, for a pharmaceutical industry with growing awareness of its responsibilities to the environment, nanotechnology can offer a sustainable pathway for the patient, the patent holder and the planet.

formulation platform for bioavailability-challenged molecules, highlighting the benefits of leon’s proprietary technology in characterisation and rapid scale-up from bench to clinic.

© leon-nanodrugs GmbH 2020
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